PROJECT SUMMARY/ABSTRACT Heart failure (HF) currently affects approximately 6 million American adults and is associated with a high risk for premature death, hospitalizations and poorer quality of life. Unlike other cardiovascular diseases such as acute myocardial infarction that has declined over time, the burden of HF is projected to increase by almost 50% by 2030. HIV-infected patients may be particularly vulnerable to developing HF, given the known higher risk of myocardial infarction and higher prevalence of vascular risk factors, antiretroviral therapy (ART)-related adverse effects, and direct effects of HIV infection, including immunodeficiency and inflammation. However, to date, HF has received very limited attention in this population. Yet, with increased survival for HIV-infected patients in the ART era, resulting in near-normal life spans, HIV-infected persons are now subject to greater risk for common age-related comorbidities, with particular concern for serious conditions such as HF. To address these key knowledge gaps, this application responds to PAR-15-280 (Multidisciplinary Studies of HIV/AIDS and Aging [R01]). This study aims to identify optimal strategies for both primary prevention of HF and improving outcomes in HIV-infected patients who develop HF. We will conduct this research within the three largest Kaiser Permanente (KP) health systems in the Cardiovascular Research Network's (CVRN) Heart Failure consortium, which has a long history of studying HF epidemiology, management and outcomes. The CVRN and KP are uniquely suited for the proposed study given the long-standing HIV registries, standardized Virtual Data Warehouse, comprehensive electronic medical record, and ability to identify carefully-matched HIV-uninfected controls from the same source population. We anticipate identifying 39,000 HIV-infected and 390,000 high-dimensional propensity-matched HIV-uninfected adults, an unprecedented sample size for a study on this topic. We propose to achieve three complementary specific aims. The first aim is to characterize the association of HIV status with the incidence of HF and HF type (reduced versus preserved ejection fraction). The second aim will investigate clinically meaningful treatment strategies for the prevention of HF and HF types in HIV-infected adults, focusing on the effect of composition and adherence to ART and long-term immunosuppression and viral replication using state-of-the-art causal modeling approaches to emulate the results of randomized trials. Finally, among new HF cases that develop among HIV-infected and HIV- uninfected adults, the third aim will examine the association of HIV status on HF-related hospitalizations and death. Given the negative impact of HF on individuals, families and health systems, we expect these results to help inform key gaps in knowledge regarding HF in HIV-infected patients, including improving primary and secondary prevention strategies in this aging population.